Abstract
Renal cell carcinoma (RCC) is responsible for most cases of the kidney cancer. Previous research showed that low serum levels of cholesterol level positively correlate with poorer RCC-specific survival outcomes. However, the underlying mechanisms and functional significance of the role of cholesterol in the development of RCC remain obscure. 3-Hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) plays a pivotal role in RCC development as it is the key rate-limiting enzyme of the cholesterol biosynthetic pathway. In this study, we demonstrated that the inhibition of HMGCR could accelerate the development of RCC tumors by lactate accumulation and angiogenesis in animal models. We identified that the inhibition of HMGCR led to an increase in glycolysis via the regulated HSP90 expression levels, thus maintaining the levels of a glycolysis rate-limiting enzyme, pyruvate kinase M2 (PKM2). Based on these findings, we reversed the HMGCR inhibition-induced tumor growth acceleration in RCC xenograft mice by suppressing glycolysis. Furthermore, the coadministration of Shikonin, a potent PKM2 inhibitor, reverted the tumor development induced by the HMGCR signaling pathway.
Highlights
Renal cancer is one of the top 10 cancers in terms of mortality and continues to increase in terms of prevalence [1]
By examining the resected tumor tissue, we found that the lactate content in the tumor tissue of the lovastatin-treated group was significantly higher by 25% ± 8.1% (p = 0.006) (Fig 1D); the levels of vascular endothelial growth factor (VEGF) and glutathione (GSH) in the tissues were significantly increased (Fig 1E and 1F)
Recent clinical and experimental research has suggested that high levels of serum cholesterol were not associated with the risk of cancer [21,22], while low levels of serum cholesterol were positively correlated with the incidence, aggressiveness, and prognosis of certain cancers including Renal cell carcinoma (RCC) [7,23,24]
Summary
Renal cancer is one of the top 10 cancers in terms of mortality and continues to increase in terms of prevalence [1]. Renal cell carcinoma (RCC) accounts for the majority of adult kidney cancers. The most effective clinical treatments for RCC are surgical resection, targeted therapy against vascular endothelial growth factor (VEGF), and immunotherapy agents such as novel kinase inhibitors [2]. Approximately 20% to 30% of patients with RCC will develop metastatic renal cell carcinoma (mRCC) after clinical diagnosis. Approximately 30% of newly diagnosed patients with localized disease experience metastases [3]. Due to tumor recurrence and metastasis, the clinical outcomes of patients with RCC have not shown satisfactory improvement over recent years [4]
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